Real-world outcomes among prostate cancer patients with BRCA2 gene variants compared to variants in other homologous DNA repair genes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17033-e17033
Author(s):  
Meghan Price ◽  
Vishal Vashistha ◽  
David Winski ◽  
Michael Kelley ◽  
Rhonda Bitting ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Real World ◽  
Specific Antigen ◽  
Brca2 Gene ◽  
Progression Free Survival ◽  
Precision Oncology ◽  
Gene Variants ◽  
Dna Repair Genes ◽  
Repair Genes

e17033 Background: PARP inhibitors (PARPis) were approved by the FDA for the treatment of advanced prostate cancer (PC) among patients (pts) harboring mutations in genes responsible for homologous DNA repair. Increasing evidence has suggested that pts with BRCA2 gene alterations may derive the most benefit from these drugs. Study objectives were to evaluate real-world treatment outcomes among Veterans prescribed PARPis for PC and to compare outcomes between pts with BRCA2 gene variants and those with variants in other homologous DNA repair genes. Methods: The U.S. Department of Veterans Affairs (VA) National Precision Oncology Program database was reviewed to identify PC pts who successfully underwent tumor DNA sequencing and were prescribed olaparib, rucaparib, niraparib or talazaporib prior to FDA approval for PARPi use in PC (May 15, 2020). Only pts who received a PARPi for > 4 weeks were included in outcome assessments The VA’s Corporate Data Warehouse was reviewed to obtain clinical and disease characteristics, laboratory and imaging reports, and treatments administered. Assessed outcomes included PSA30, defined as the percentage of pts achieving 30% reduction in prostate-specific antigen (PSA) level, and composite progression-free survival (PFS), which included time to radiographic progression per RECIST criteria, discontinuation of therapy, and/or death. Pts who discontinued therapy due to toxicity were censored for PFS analyses. PSA30 and PFS were compared between pts bearing BRCA2 gene variants and those with variants in other homologous DNA repair genes using t-testing and log-rank testing, respectively. Results: 48 pts were prescribed a PARPi for PC; 43 (89.6%) received therapy for > 4 weeks. BRCA2 gene variants (43.8%) were most commonly observed followed by ATM (23.0%) and BRCA1 (16.7%). Forty-two pts (87.5%) received prior systemic therapy beyond androgen deprivation. Forty (83.3%) pts received olaparib, 6 (12.5%) received rucaparib, and 2 (4.2%) received both. Eleven (22.9%) discontinued therapy due to toxicity, with anemia being most common toxicity. Of the 43 pts treated for > 4 weeks, pts with BRCA2 variants had a higher rate of PSA30 than those without (47.9% vs. 4.5%; p = 0.004). The median PFS for all pts was 4.0 months. Pts with BRCA2 gene variants had longer PFS than those without BRCA2 gene variants (7.2 vs 3.3 months; p = 0.037). Pts with BRCA2 gene variants also had longer PFS than those with BRCA1 variants (7.2 vs 3.3, p = 0.031). No difference was observed in PFS between those with BRCA2 variants and those with ATM variants ( p = 0.51). Conclusions: Approximately one-quarter of PC pts with variants in homologous DNA repair genes treated with PARPis achieve a 30% reduction in PSA, and the median PFS is 4 months. Pts harboring BRCA2 gene variants have a significantly higher rate of PSA30 and a longer PFS than those with variants in other homologous DNA repair genes.

scholarly journals Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer

2020 ◽  
Author(s):  
Burcu F Darst ◽  
Tokhir Dadaev ◽  
Ed Saunders ◽  
Xin Sheng ◽  
Peggy Wan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Statistical Tests ◽  
European Ancestry ◽  
International Studies ◽  
Dna Repair Genes ◽  
Variant Gene ◽  
Significant Gene ◽  
Repair Genes

Abstract Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. Methods Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

Abstract 2753: Landscape of somatic mutations in DNA repair genes in prostate cancer

2016 ◽  
Author(s):  
Santosh Yadav ◽  
Muralidharan Anbalagan ◽  
Melody Baddoo ◽  
Erik Flemington ◽  
Krzysztof Moroz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Somatic Mutations ◽  
Dna Repair Genes ◽  
Repair Genes

Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer

2020 ◽  
Vol 3 (2) ◽  
pp. 224-230 ◽  
Author(s):  
Yishuo Wu ◽  
Hongjie Yu ◽  
Shuwei Li ◽  
Kathleen Wiley ◽  
S. Lilly Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Grade Group ◽  
Pathogenic Mutations ◽  
Group 5 ◽  
Repair Genes

Inherited mutations in DNA repair genes in men with metastatic castration-resistant prostate cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5009-5009 ◽  
Author(s):  
Peter Nelson ◽  
Joaquin Mateo ◽  
Himisha Beltran ◽  
Navonil De Sarkar ◽  
Olivier Elemento ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Inherited Mutations ◽  
Repair Genes

Copy number variations in AR-associated and DNA repair genes from plasma cell-free DNA of metastatic CRPC patients.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Ratish Gambhira ◽  
Elisa M. Ledet ◽  
Aryeneesh Dotiwala ◽  
Diptasri Mandal ◽  
A. Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Progression ◽  
Copy Number ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Dna Repair Genes ◽  
Prostate Cancer Progression ◽  
Free Dna ◽  
Repair Genes

281 Background: Cell-free DNA (cfDNA) present in the plasma of advanced cancer patients can reflect tumor related genetic alterations. Recent data suggests copy number variations (CNVs) in AR-associated and DNA repair pathway genes play a potential role in prostate cancer progression. Here, we performed sequencing of cfDNA from 13 mCRPC patients to evaluate its potential in elucidating tumor related genetic variations. The long-term goal of our project is to correlate cfDNA derived genetic alterations with prostate cancer progression and/or therapeutic resistance/responses. Methods: cfDNA was isolated from 13 advanced mCRPC patient plasma samples using the Qiagen circulating nucleic acid kit. 100ng of cfDNA was utilized for library construction; and the libraries were paired-end sequenced on the Illumina HiSeq 2000. The resulting data was analyzed using the GATK best practices bioinformatics pipeline and the visualized using the SNP & Variation Suite v8.x. Results: The bioanalyzer profiles of cfDNA derived from mCRPC patients is highly fragmented with an average fragment size of 306-605bp. Although, several CNVs were found across the genome, we focused analysis on CNVs related to AR associated and DNA repair genes. Our preliminary analysis of cfDNA, despite low sequencing depth, shows full or partial amplifications in AR (13/13), and other genes including FOXA1, NCOR1, NCOR2 and/or PIK3CA (7/13) and NCOR2 (10/13). For DNA repair genes partial/full amplifications were present in BRAC1, BRAC2, ATM, CDK12, MLH1 and/or MSH2 (7/13). Deletions are less reliably detected in the highly fragmented cfDNA. The majority of these CNVs have been reported in the WGS studies from metastatic CRPC tissue derived genomic DNA (cBioPortal). We are currently validating cfDNA genomic alterations by comparing it to germ line DNA derived via qPCR. Conclusions: Our preliminary study indicates that AR and DNA repair related genetic alterations could be found in the cfDNA derived from metastatic CRPC patients. This warrants more detailed examination of these cfDNA genetic alterations for identifying clinically relevant issues in mCRPC patients.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Elisa Marie Ledet ◽  
Ellen Jaeger ◽  
Whitley Hatton ◽  
Marcus W. Moses ◽  
Alexandra Sokolova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Family History ◽  
Metastatic Prostate Cancer ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Brca Mutations ◽  
Repair Genes

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p < 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with >1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with >2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of >2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.

Sign in / Sign up

Export Citation Format

Share Document